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Molecular Pharmacology

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Research ArticleArticle

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence

Boying Guo, Alicia Rodriguez-Gabin, Andrea Prota, Tobias Mühlethaler, Nan Zhang, Kenny Ye, Michel O Steinmetz, Susan Band Horwitz, Amos B Smith III and Hayley McDaid
Molecular Pharmacology June 26, 2020, mol.119.117457; DOI: https://doi.org/10.1124/mol.119.117457
Boying Guo
1 University of Pennsylvania;
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Alicia Rodriguez-Gabin
2 Albert Einstein College of Medicine;
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Andrea Prota
3 Paul Scherrer Institut;
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Tobias Mühlethaler
3 Paul Scherrer Institut;
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Nan Zhang
1 University of Pennsylvania;
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Kenny Ye
2 Albert Einstein College of Medicine;
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Michel O Steinmetz
4 University of Basel;
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Susan Band Horwitz
2 Albert Einstein College of Medicine;
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Amos B Smith III
1 University of Pennsylvania;
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Hayley McDaid
5 Albert Einstein College of medicine
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Abstract

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers; malignancies that typically succumb to taxane-resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anti-cancer activity; thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anti-cancer efficacy relative to Taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated (i) improved pharmacologic properties, specifically, increased EMax and AUC, and decreased EC50; (ii) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to Taxol or DDM; (iii) reduced propensity for senescence induction relative to DDM; (iv) superior long-term activity in cancer cells versus Taxol or DDM, and (v) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a high-efficiency DDM congener with broad range anti-cancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence.

SIGNIFICANCE STATEMENT Here, we describe the anti-cancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and -resistant cancer cell models, diminished risk of chemotherapy-mediated senescence and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to β-tubulin that could account for the improved anti-cancer activity. These findings support continued pre-clinical development of discodermolide, particularly in the chemorefractory setting.

  • Cancer chemotherapy
  • Cell proliferation
  • Chemotherapy
  • Cytoskeleton
  • Drug development
  • Microtubules
  • X-ray crystallography
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Research ArticleArticle

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence

Boying Guo, Alicia Rodriguez-Gabin, Andrea Prota, Tobias Mühlethaler, Nan Zhang, Kenny Ye, Michel O Steinmetz, Susan Band Horwitz, Amos B Smith and Hayley McDaid
Molecular Pharmacology June 26, 2020, mol.119.117457; DOI: https://doi.org/10.1124/mol.119.117457

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Research ArticleArticle

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence

Boying Guo, Alicia Rodriguez-Gabin, Andrea Prota, Tobias Mühlethaler, Nan Zhang, Kenny Ye, Michel O Steinmetz, Susan Band Horwitz, Amos B Smith and Hayley McDaid
Molecular Pharmacology June 26, 2020, mol.119.117457; DOI: https://doi.org/10.1124/mol.119.117457
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